Translational Science Ground Zero

Many researchers who apply for NIH grants will recognize the phrase: “Completion of this research will lead to new therapeutic targets and strategies.” The University of Illinois at Chicago receives over $100 million in NIH funding per year, and a large number of these grants are based on target- or drug- discovery. The problem is that researchers are not making drugs.

Investigators across the country use NIH funding to identify proteins that reduce or eliminate disease characteristics. However, most will never advance these findings along the drug innovation pipeline and begin to build biochemical assays as an initial step towards a small-molecule drug discovery effort.

“Before clinical trials, before proof of concept animal studies, there has to be a focus on drug discovery,” said Jason Hickok, PhD, Assistant Professor in the Department of Medical Chemistry and Pharmacognosy.

Researchers studying the molecular biology of a disease typically focus on a protein and then perform genetic manipulations to increase or decrease its expression. In turn, this can reduce the disease condition in their model.

“While this is an important step in validating a target or pathway, the problem is these techniques cannot be used as therapies,” explains Hickok. “Developing a compound that might mimic the results of a genetic deletion is an entirely different skill set.”

Even when investigators properly orient their research towards developing a therapy, the process of translating the basic science underlying disease etiology to clinical practice is so daunting that it is appropriately referred to as the “valley of death.” In 2015, the Tufts Center for the Study of Drug Development estimated the average cost of drug development from inception to market at a staggering $2.6 billion.

“Attrition rates in drug discovery have been costly, and big pharma has slashed R&D budgets in an effort to de-risk drug development,” says Greg Thatcher, PhD, Director of UICentre. “As a result, the focus of preclinical drug discovery has shifted to academic drug discovery centers.”

The UIC Collaborative Engagement in Novel Therapeutic Research and Enterprise, or UICentre, is a campus-wide drug discovery program centered on collaborative engagement that stimulates and enhances the application of chemical, pharmaceutical, and translational knowledge. Working in tandem with the Center for Clinical and Translational Science, the goal is to elevate the biomedical discoveries at UIC to a level where they can be translated to clinical practice and improve the health of society.

Within drug discovery there is a greater philosophical question of whether or not universities should be involved in translational science at all. Should academic medical centers have a dual role of training the next generation of clinicians and scientists while simultaneously developing for-profit products? Can universities pursue both truth and money?

Moreover, if an institution chooses to pursue drug discovery, how is this accomplished? The process requires a robust and diverse team of clinicians, biologists, chemists and administrators.

“You don’t need to be a scientist to be involved in getting a drug to market. People who market, communicate and secure start-up funds are just as important as the chemists,” said Hickok, who serves as the Assistant Director of the UICentre.

These complex, multidisciplinary teams do not spring up organically. UICentre’s organizational model has evolved to bring together members from across UIC with varied skill sets and provides seed funding, external expertise, project management, and core services including bioassay development, high throughput screening, and drug metabolism and pharmacokinetic (DMPK) studies.

“Drug development is collaborative by nature,” said Thatcher. “The success or failure of this endeavor rests in the willingness of researchers at UIC to engage in team science and to capitalize on the capabilities and expertise of both colleagues and external consultants.”

UICentre uses seed funding to expand projects from individual UIC labs that are open to developing novel small molecules. Most projects in laboratories around campus are in the very early phases of drug discovery; few have begun to venture into the “valley of death.”

Due to the expense and limited funding for bioassays, early development work often relies on data from a relatively limited sample size. Unfortunately, while data from these limited sample sets can qualify an assay or model for publication in even the most prestigious journals, the models often are not robust enough to use in the drug discovery process. Reproducibility of results is a major concern.

Hickok explained, “Once you dig into the data and repeat the multiple times in two different people’s hands, you find that the assay cannot be miniaturized for higher throughput or cannot be statistically validated.”

In spite of these challenges, UICentre has achieved some success. Since its inception in 2012, UICentre was involved in the submission of $32 million in grants with a 41% funding rate. They have collaborated with over 46 campus PIs from the Colleges of Medicine, Pharmacy, Nursing, and Liberal Arts and Sciences. UICentre also actively engages with the Office of Technology Management to move their research discoveries into marketable intellectual property for the university.

Organizations like UICentre and the CCTS are trying to promote awareness of the fact that NIH and other funding institutions are no longer interested simply in the molecular function of diseases; they want cures. UICentre and the CCTS encourage basic scientists to think about the translational application of their research project from conception. The valley of death is real, but campus centers that promote team science can facilitate the large-scale collaborations necessary to help bridge the gaps in the translational process.

Hickok stated, “The whole purpose of health research is to find cures. Every new research finding is a potential path to a new health innovation, but we need to work together to make it happen.”